The membrane-associated E3 ubiquitin ligase MARCH3 downregulates the IL-6 receptor and suppresses colitis-associated carcinogenesis.

Cell Mol Immunol

Department of Infectious Diseases, Zhongnan Hospital of Wuhan University; Medical Research Institute; Frontier Science Center for Immunology and Metabolism; Research Unit of Innate Immune and Inflammatory Diseases, Chinese Academy of Medical Sciences; Wuhan University, Wuhan, 430071, China.

Published: December 2021

The IL-6-STAT3 axis is critically involved in inflammation-associated carcinogenesis (IAC). How this axis is regulated to modulate IAC remains unknown. Here, we show that the plasma membrane-associated E3 ubiquitin ligase MARCH3 negatively regulates STAT3 activation triggered by IL-6, as well as another IL-6 subfamily member, Oncostatin M (OSM). MARCH3 is associated with the IL-6 receptor α-chain (IL-6Rα) and its coreceptor gp130. Biochemical experiments indicated that MARCH3 mediates the polyubiquitination of IL-6Rα at K401 and gp130 at K849 following IL-6 stimulation, leading to their translocation to and degradation in lysosomes. MARCH3 deficiency increases IL-6- and OSM-triggered activation of STAT3 and induction of downstream effector genes in various cell types. MARCH3 deficiency enhances dextran sulfate sodium (DSS)-induced STAT3 activation, increases the expression of inflammatory cytokines, and exacerbates colitis, as well as azoxymethane (AOM)/DSS-induced colitis-associated cancer in mice. In addition, MARCH3 is downregulated in human colorectal cancer tissues and associated with poor survival across different cancer types. Our findings suggest that MARCH3 is a pivotal negative regulator of IL-6-induced STAT3 activation, inflammation, and inflammation-associated carcinogenesis.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8632971PMC
http://dx.doi.org/10.1038/s41423-021-00799-1DOI Listing

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